Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA progression. Our previous studies have demonstrated that transcription factor FOXM1 is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated FOXM1 expression. In sharp contrast, our recent study has shown a consistent lack of vitamin D receptor (VDR) expression in invasive PDA as compared to that in PanINs. Causally linking VDR loss to FOXM1 overexpression and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression. We postulate that downregulation of VDR expression causes FOXM1 overexpression and consequential acquisition of malignant phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of VDR signaling could attenuate PanINs progression and sensitize PDA to Vitamin D treatment. To test our hypothesis, we propose three specific aims: (1) Determine whether loss of VDR expression is a critical event of pancreatic cancer progression from PanIN to invasive PDA; (2) Determine the critical molecular mechanisms underlying dysregulation of VDR signaling in and its mechanistic impact on PDA progression; and (3) Determine whether an intact VDR signaling renders PanINs sensitive to Vitamin D treatment, while invasive PDA are refractory to Vitamin D due to loss of VDR expression. These three novel specific aims with clinical relevant question (aim 1), mechanistic substantiation (aim 2) and translational validation (aim 3), are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. Our proposed studies will take advantage of the unique resources available at MD Anderson Cancer Center, including our large collection of pancreatic cancer specimens and mouse models. Given the important role of VDR/FOXM1 we have uncovered, we predict that completion of these studies will provide insightful information for the molecular basis of pancreatic cancer progression and for identification of molecular targets to design effective prevention and treatment strategies; and translation of our findings into benefiting PDA patients is our long term goal.